Messenger RNAs (mRNA) are linear molecules that contain
instructions for producing the proteins that keep living cells
functioning.
A new study by researchers from UCL and Cancer Research UK's
London Research Institute (now the Francis Crick Institute) has
shown how the three-dimensional structures of mRNAs determine their
stability and efficiency inside cells.
This new knowledge could help to explain how seemingly minor
mutations that alter mRNA structure might cause things to go wrong
in neurodegenerative diseases like
Alzheimer's.
mRNAs carry genetic information from DNA to be translated into
proteins. They are generated as long chains of molecules, but they
fold up into complex structures by making connections between
different sections of the chain. Despite the importance of these
structures to how mRNAs function, very little was known about them
until now.
The study reports a new technique allowing scientists to
identify connections that hook sections of an mRNA together. "We
were amazed to find that mRNAs make thousands of connections inside
living cells", said Professor Jernej Ule of UCL (University College
London) who led the research with Dr Nicholas Luscombe of UCL and
Cancer Research UK's London Research Institute. "Sometimes these
connections hook together very distant parts of mRNA
molecules."
Further investigation showed that these connections affect how
mRNAs interact with other molecules inside cells, and so influence
how much protein they eventually produce.
A particularly important connection is found in an mRNA that
codes for a protein called X-box binding protein
1.
"This protein enables our cells respond to stress. The amount of
this protein in cells is tightly controlled, but when this control
is lost, it can contribute to neurodegenerative diseases such as
Alzheimer's," explained Yoichiro Sugimoto, who was a PhD student
with Ule at the Medical Research Council's Laboratory of Medical
Biology in Cambridge. "The connection we found in the mRNA helps to
ensure that the right amount of protein is
produced."
Genetic mutations in mRNAs can lead to faulty connections and
cause the wrong amounts of protein to be produced. This suggests
that a wide range of human diseases could be caused by such
mutations. "The NHS's 100,000 Genomes Project is helping us
discover where potentially harmful mutations happen in the human
genome," said Dr Luscombe. "Finding those mutations that impact
mRNA structure will help us understand why things go wrong in
diseases like Alzheimer's and cancer."
"This has great potential!" adds Professor Ule. "Because
understanding the genetic cause is the first step towards finding
new ways to treat these diseases."
The paper, hiCLIP reveals the in vivo atlas of mRNA secondary structures
recognized by Staufen 1, is published inNature.